In 1990 we identified a child with a disorder involving dramatic enlargement of all her lymph node chains, hepatomegaly, splenomegaly, autoimmune hemolytic anemia and marked expansion of CD3+/CD4-/CD8- T cells. We have termed this disorder autoimmune lymphoproliferative syndrome, or ALPS. We subsequently identified eight additional children and 2 adults with similar disorders; their clinical and immunologic features were well-studied. Heritable, functional mutations in the gene encoding Fas, a cell surface protein involved in lymphocyte apoptosis were identified in 7 of the cases and in 14 unaffected relatives; 3 ALPS patients have no mutations in Fas or its ligand. Defective T and B cell apoptosis was demonstrated for all subjects. Detailed analysis of immune function shows ALPS patients to exhibit a predominant Th2 cytokine profile, with markedly elevated circulating IL-10 and decreased monocyte release of IL-12. This is the first genetic disorder involving apoptosis and the first human gene in which a defect leads to autoimmune disease. We will be analyzing other proteins related to apoptosis to determine whether they contribute to ALPS.